Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

ARIMIDEX: a potent and selective aromatase inhibitor for the treatment of advanced breast cancer.

Aromatase inhibitors have been available for a number of years and their ability to reduce circulating estradiol levels has been shown to produce clinical benefit in women with advanced breast cancer. Until recently, the only commercially available aromatase inhibitor was aminoglutethimide. Although aminoglutethimide has been shown to be efficacious in the treatment of advanced breast cancer, it does cause significant toxicity and requires the use of concomitant hydrocortisone therapy. Anastrozole is one of a new class of potent aromatase inhibitors able to suppress estradiol to the limit of detection of sensitive assays without suppressing adrenal steroidal synthesis. Two large clinical trials (n = 764) conducted in the U.S.A. and in Europe evaluated two doses of anastrozole, 1 and 10 mg a day, compared to megesterol acetate, 40 mg four times a day, in postmenopausal women who had progressed while on tamoxifen. Response rates and time to progression with anastrozole were similar to those of megesterol acetate. Objective responses (CR + PR) were 10.3%, 8.9% and 7.9% in the 1 and 10 mg of anastrozole and megesterol acetate treatment groups, respectively. Another 25.2%, 22.6% and 26.1% had stable disease for over 24 weeks on 1, 10 mg anastrozole and megesterol acetate, respectively. Anastrozole and megesterol acetate were well tolerated; however, more patients had significant weight gain on megesterol acetate than with anastrozole treatment. The weight gain seen with megesterol acetate continued to increase over time. Anastrozole has a better therapeutic index (fewer side-effects) and has recently been approved by the FDA and a number of other regulatory agencies around the world for the treatment of advanced breast cancer.

Aromatase inhibitors in metastatic breast cancer.

Inhibition of estrogen production or actions provides an effective therapy for patients with hormone-dependent breast cancer. A number of approaches to accomplishing these goals are available, and each has its own advantages and disadvantages. Aromatase inhibitors are capable of lowering estrogen levels in postmenopausal women whose estrogen production is not ovarian. Aromatase, the enzyme that converts androgens to estrogens, is one of a series of related P-450 enzymes involved in the production of steroid hormones. Because of the similarity of the P-450 enzymes, selectivity is important; nonselective aromatase inhibitors, such as aminoglutethimide, can affect enzymes controlling the production of other steroids and lead to significant side effects. Recently, a number of newer aromatase inhibitors have been synthesized and are in preclinical or clinical development. In early 1996, anastrozole became available for clinical use in the United States and in a number of other countries. In phase I studies, anastrozole was shown to be highly selective and inhibited estrogen production in postmenopausal patients to levels below the detection threshold of the assay. Another aromatase inhibitor in advanced development is fadrozole. In this review we present briefly the available clinical data on fadrozole and anastrozole.

Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group.

PURPOSE: To compare the efficacy and tolerability of anastrozole (1 and 10 mg once daily), a selective, oral, nonsteroidal aromatase inhibitor, and megestrol acetate (40 mg four times daily), in postmenopausal women who progressed following tamoxifen treatment. PATIENTS AND METHODS: Two randomized, double-blind for anastrozole, open-label for megestrol acetate, parallel-group, multicenter trials were conducted in 764 patients. Because both trials were identical in design, an analysis of the combined results was performed to strengthen interpretation of results from each trial. RESULTS: The median follow-up duration was approximately 6 months. The estimated progression hazards ratios were 0.97 (97.5% confidence interval [CI], 0.75 to 1.24) for anastrozole 1 mg versus megestrol acetate and 0.92 (97.5% CI, 0.71 to 1.19) for anastrozole 10 mg versus megestrol acetate. The overall median time to progression was approximately 21 weeks. Approximately one third of patients in each group benefited from treatment. Twenty-seven patients (10.3%) in the anastrozole 1-mg group, 22 (8.9%) in the anastrozole 10-mg group, and 20 (7.9%) in the megestrol acetate group had a complete or partial response, and 66 (25.1%), 56 (22.6%), and 66 (26.1%) patients, respectively, had stable disease for > or = 24 weeks. For all end points, individual trial results were similar to the results of the combined analysis. Anastrozole and megestrol acetate were well tolerated. Gastrointestinal disturbance was more common among patients in the anastrozole groups than the megestrol acetate group; the difference between the anastrozole 10 mg and megestrol acetate groups was significant (P = .005). Significantly fewer patients in the anastrozole 1-mg (P < .0001) and 10-mg (P < .002) groups had weight gain than in the megestrol acetate group. More than 30% of megestrol acetate-treated patients had weight gain > or = 5%, and 10% of patients had weight gain > or = 10%. Patients who received megestrol acetate continued to gain weight over time. CONCLUSION: Anastrozole, 1 and 10 mg once daily, is well tolerated and as effective as megestrol acetate in the treatment of postmenopausal women with advanced breast cancer who progressed following tamoxifen treatment. Moreover, anastrozole therapy avoids the weight gain associated with megestrol acetate treatment.

ARIMIDEX: a new oral, once-a-day aromatase inhibitor.

ARIMIDEX is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies examining the pharmacology of ARIMIDEX were conducted in both animals and humans. In animals, ARIMIDEX elicits maximal aromatase suppressive activity at a dose of approx. 0.1 mg/kg, does not alter adrenal steroid hormone biosynthesis, and at a dose of 1 mg/kg, has no other pharmacologic effects other than aromatase inhibition. In this overview, the pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple daily doses of ARIMIDEX are reported in humans. Daily doses of 1-10 mg of ARIMIDEX suppressed estradiol levels to the maximum degree measurable using sensitive estrogen assays. ARIMIDEX had no clinically significant effects on the response of cortisol and aldosterone to ACTH stimulation. Absorption of ARIMIDEX was rapid, with maximum plasma concentrations occurring within 2 h after oral administration. Plasma concentrations of ARIMIDEX rose with increasing doses of the drug. The elimination half-life of ARIMIDEX in humans ranged from 30 to 60 h. Consistent with the long plasma half-life, steady state plasma concentrations were 3-4-fold higher than plasma concentrations observed after single administration of 1, 3, 5, or 10 mg doses. Long term treatment of breast cancer patients with 10 mg/day has continued in 17 patients without an escape of estradiol suppression. Previously, these patients had received on average 2.6 systemic treatments for breast cancer and had significant metastatic disease. Three of the 17 patients continued ARIMIDEX treatment for 20 months and beyond. Given the number of previous treatments and tumor burden at the start of treatment, the response to ARIMIDEX treatment is encouraging. Phase III studies are now underway to assess the efficacy and safety of ARIMIDEX in the treatment of advanced breast cancer.

Arimidex: a potent and selective fourth-generation aromatase inhibitor.

Arimidex is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies to determine the pharmacology of Arimidex were conducted in both animals and humans. In animals, Arimidex was selective for the aromatase enzyme, elicited maximal activity at about 0.1 mg/kg, did not interfere with steroid hormones produced by the adrenal glands, and, at a dose of 1 mg/kg, had no detectable pharmacologic activity other than aromatase inhibition. Absorption of ZD1033, the active component of Arimidex, was rapid and virtually complete after oral administration to animals. ZD1033 was extensively metabolized in animals after oral administration; the metabolites were excreted predominantly in urine. The pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple daily doses of Arimidex were determined in humans. Doses of 1 to 10 mg of Arimidex suppressed estradiol to the maximum degree measurable. Arimidex had no clinically significant effects on key enzymes that regulate cortisol and aldosterone biosynthesis. Absorption of ZD1033 was rapid, with maximum plasma concentrations occurring within 2 hours after oral administration. Plasma concentrations of ZD1033 rose with increasing doses of Arimidex. The elimination half-life of ZD1033 in humans ranged from 30 to 60 hours. Urinary excretion accounted for a small percentage of each dose. A 3- to 4-fold accumulation of ZD1033 in plasma occurred after daily administration of 3-, 5-, or 10-mg doses. Arimidex was well tolerated. Phase III studies are under way to determine the efficacy and safety of Arimidex in postmenopausal women with advanced breast cancer.

Thallium-technetium parathyroid scan. A useful noninvasive technique for localization of abnormal parathyroid tissue.

We studied the usefulness of the thallium-technetium scan in 60 patients with suspected parathyroid disorders. The scan correctly localized abnormal parathyroid tissue in 82% of patients with surgically proved primary hyperparathyroidism due to a single adenoma and in 60% of patients operated on for primary hyperplasia. The scan was particularly useful in patients who had undergone previous neck explorations, since it successfully identified residual adenomatous or hyperplastic tissue in six of seven patients. False-positive images were consistently produced in all patients with coexisting thyroid disease. We conclude that the thallium-technetium scan is useful for localizing abnormal parathyroid tissue. We recommend its routine use in patients with persistent or recurrent hypercalcemia following neck exploration for primary hyperparathyroidism who have no evidence of thyroid disorders.

Impotence associated with low biological to immunological ratio of luteinizing hormone in a man with a pituitary stone.

Quantitative reduction in LH secretion resulting from hypothalamic-pituitary dysfunction is a known cause of impotence. Qualitative abnormalities of secreted LH, however, have not been described under these circumstances. During evaluation of a 39-yr-old man with impotence and a calcified pituitary mass (pituitary stone), we detected a qualitative abnormality of LH characterized by a low ratio of bio- to immunoactivity (B:I). Initial work-up revealed basal morning serum testosterone levels of 2.14, 3.18, 3.97, and 3.11 ng/ml on 4 separate days, low to low normal urinary LH (300, 200, and 478 mIU/h), and normal GH, TSH, PRL, and ACTH secretion after provocative testing. The response of impotence to testosterone but not placebo in a double blind trial confirmed the clinical significance of the borderline low androgen levels. These findings prompted a systematic analysis of 24-h LH pulses as well as clomiphene and GnRH responsiveness. By RIA, mean serum LH levels [9.1 +/- 0.3 (+/- SE) mIU/ml] and all other response parameters were normal. In striking contrast, mean serum LH by bioassay was low (9.9 +/- 0.4 mIU/ml vs. 41.4 +/- 5.7 in normal subjects), as were B:I ratios (1.0 +/- 0.03 vs. control values of 3.1 +/- 0.5 to 5.3 +/- 0.3). Only during maneuvers designed to increase GnRH were B:I ratios increased to 3.3 +/- 0.22 (exogenous GnRH) and 1.8 +/- 0.12 (clomiphene). Mean testosterone levels before and after exogenous GnRH treatment were 3.28 +/- 0.24 and 4.76 +/- 0.16, respectively (P less than 0.001). The results suggest an association between the low LH B:I ratio and the anatomical disruption of the hypothalamic-pituitary portal system by the pituitary stone. The increased B:I ratio during GnRH or clomiphene administration indicates a functional link between pituitary GnRH exposure and the greater potency of the LH secreted.

Acanthosis nigricans and insulin resistance.

Acanthosis nigricans has been reported in association with many conditions and most recently with insulin resistance. A case is presented to illustrate the clinical characteristics of acanthosis nigricans and insulin resistance. The various subtypes of this syndrome complex and its pathogenic mechanisms are reviewed.

Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies.

Twelve boys, aged 12 to 19 years, with persistent gynecomastia were treated with the antiestrogen, clomiphene citrate, at a dose of 50 mg/day by mouth for one to three months. The mean breast size decreased by 0% to 36%, with only five boys experiencing a reduction of greater than 20%. Five boys subsequently required reduction mammoplasty. Levels of urinary gonadotropins, serum testosterone, and estradiol increased significantly during therapy. Since the ratio of testosterone to estradiol remained unchanged during treatment, the antiestrogen effects were achieved primarily at the level of breast tissue. Clomiphene citrate in a dose of 50 mg/day resulted in only small decreases in persistent pubertal gynecomastia and was not a satisfactory medical therapy for the condition.